We have earlier demonstrated for the first time that endocannabinoids acting via CB1 receptors promote voluntary alcohol drinking in an age-dependent manner, using a mouse model of two bottle/free choice paradigm(PNAS 100:1393, 2003. The brain-penetrant CB1 inverse agonist rimonabant used in this study was subsequently introduced as a treatment of obesity, but had to be wihdrawn from the pharmaceutical market in 2008, due to neuropsychiatric side effects, including anxiety, depression and suicidal ideation. An alternative approach, championed by my laboratory, was the introduction of peripherally restricted CB1 inverse agonists that retained the metabolic efficacy of rimonabant but were devoid of its neurobehavioral effects in rodent models of the metabolic syndrome. Paradoxically, such compounds were also found to reduce food intake, a centrally mediated effect. This paradox was resolved by the demonstration that peripheral CB1 blockade in diet-induced obese mice rapidly reversed their leptin resistance by reversing their hyperleptinemia, via inhibiting leptin production in adipose tissue and increasing leptin clearance in the kidney. This made us to wonder whether the high alcohol preference of C57Bl6 mice, another central function promoted by CB1 activation, may also be affected indirectly through blockade of CB1 in the periphery. A possible mechanism involves ghrelin, a gastric peptide that promotes appetite via ghrelin receptors in the brain. Preliminary experiments indicate that rimonabant and two non brain-penetrant CB1 inverse agonists, JD5037 and our own compound MRI-1569, were equieffective in markedly reducing total alcohol intake as well as ethanol preference in C57BL6 mice, using a two bottle, free choice paradigm. Furthermore, CB1 blockade significantly reduced plasma levels of total as well as acetylated ghrelin. We are now testing the effects of these compounds in ghrelin knockout as well as ghrelin receptor knockout mice obtained from Roy G Smith at Scripps. We are also testing CB1 regulation of ghrelin release in isolated stomach preparations. The compounds are also tested in an operant drinking paradigm in collaboration with dr. Andrew Holmes.